The goal of this project is to develop a novel oral neonatal combination TB-HIV vaccine prime, and rMVA-HIV boost, to protect infants against both HIV infection via breast-milk, and Mycobacterium tuberculosis infection. Perinatal mother to child HIV transmission occurs in 1 of 4 children born to HIV-infected women, and accounts for upwards of 90% of all pediatric HIV infections . HIV and TB infections disproportionately affects developing countries like India. The hypothesis is that live attenuated rAMtb-HIV prime/rMVA-HIV boost combination should be safe in newborns, and should induce long-lasting central memory responses that are protective against both HIV and TB. The overall objective of this proposal is to avert vertical transmission of HIV by breast milk and reduce childhood mortality rates by using a novel oral highly attenuated proapoptotic M. tuberculosis (Mtb) vaccine expressing HIV-1 Clade C antigens that will augment the magnitude, persistence and proportion of polyfunctional HIV-specific T cell responses after TBC-M4 vaccine (recombinant MVA that encodes env, gag, tat, rev, nef and ?RT gene sequences from subtype C virus isolates) boosting (or vice versa) among sites relevant to protection against breast milk HIV transmission. This proposal will be submitted in response to the NIH Indo-U.S. Vaccine Action Program (VAP) (R03) RFA in collaboration with Tuberculosis Research center (Indian Council of Medical Research), and will aim to facilitate a collaboration between AECOM and ICMR scientists to develop this strategy. The major hypothesis to be tested is whether a safe rAMtb-HIV-C prime and rMVA-HIVC boost strategy elicits long lasting central T cell memory responses after neonatal immunization. We will test these hypotheses in a neonatal mouse model in two specific Aims: Aim 1: To determine which of the two deletions in distinct Mycobacterium tuberculosis (Mtb) genes that encode apoptotic interference pathways, ?nuoG or ?secA2, in a novel recombinant Mtb vaccine candidate containing double attenuating auxotrophic deletions mc26434 (?panCD ?leuCD) and expressing HIV-1 Clade C antigens results in the highest frequency polyfunctional CD8+ and CD4+ T cell responses against TB and HIV-1. Aim 2: We will test whichever strain that generates the highest frequency responses in a in a neonatal prime-boost regimen with rMVA (TBC-M4), to attempt to establish robust and long lasting memory T cell responses against both HIV and TB at the earliest time point after birth. This study paves the way for identifying a vaccine regimen to protect against BM HIV-1 Clade C transmission and TB in infants. The long term outcome of these studies may yield a vaccination strategy that is effective against both infant breast milk HIV transmission and TB infection.